baran gm 03/17/12 triquinanes: hirsutene, isocomene ...baran gm 03/17/12 triquinanes: hirsutene,...

Propellane Triquinane

Modhephene 13-OAc-Modhephene Modhephene epoxide

Linear Triquinane

Hirsutene

H H

H

H

H H

CapnelleneHypnophylin

[3.3.3] carbon skeleton

OAc

OCHOO

Pulicaral

[6.3.0.02,6] undecane carbon skeleton

H

H

OHO

O

O

CoriolinOH

H

H

HO2C X

O

X = H, OH Hirsutic acidX = O Complicatic acid

H

H

O

O

OH

H

H

Cerapicol

HO

HCO2H

Pentalenic Acid

H

X = H2 Silphiperfol-6-eneX = O Silphiperfol-6-en-5-one

H

Silphiperfol-5-en-3-ol

HO

Subergorgic acid

HO2C

O

HHO2C

O

H

Cantabrenoic acid

OHO2C

HO

H

Epoxycantaboic acid

HO2CH

Cantabrenoic acid Cantabradienoic acid

H

H

O

Cucumin EO

H

H OH

Ceratopicanol

H

H

HO2C

O

O

Pleurotellol

Angular Triquinane

Isocomene

[6.3.0.01,5] undecane carbon skeleton

!"Isocomene

H

Silphinene

H

3-Oxosilphinene

O

H

H

Pentalenene

H

Senoxydene

Triquinanes as "hot" targets for different research groups. Only the syntheses of jasmone and later taxol found wider interest.

Triquinane area: 1980 - 1990 (more than 130 different syntheses)Biological activity: moderate

Triquinanes as playground for the development of new methodologies for the synthesis of 5-membered rings:- Curran: radical cyclization strategy- Wender: arene-olefin meta photocycloaddition - Paquette: inspired by [3+2] annulation of Helquist- Hudlicky: [4+1] diene-carbene annulation and [3+2] dienolate-enone annulation- Metha: olefin metathesis strategy- Rawal: photocycloaddition - fragmentation- Oppolzer: intramolecular ene reaction- Little: intramolecular 1,3-diyl cycloaddition

H

HO H

H

Connatusin A

HO

O

OHH

H

H

Connatusin B

OHO

OHHO

XHHO OH

Triquinanes: Hirsutene, Isocomene, ModhepheneBaran GM 03/17/12 Karin Weidner

Hudlicky 1980Intramolecular [4+1] cyclopentene annulation

CHOOH

CO2HON2

H

O

H

H O

H

H

O

5 steps

Cu(acac)2

97%

O

H

+

1A. H2, Pt1B. RhCl3, H2, PtO22. Ph3P=CH2

Mehta 1981Diels-Alder cycloaddition, photochemical [2+2] cycloaddition, thermal [2+2] cycloreversion

Little 1981Intramolecular 1,3-diyl cycloaddition

O

O

O

4 steps CO2Me

NN

CO2Me

H

H

CO2CH3H

Ley 1982Organoselenium mediated cyclization

Magnus 1982Organosilicon mediated key step

PbCO3560 °C

1B: 11%H

H

H

O

CH2=CHMgBr

1. CH3C(OEt)3, Hg(OAc)2 CH3CH2CO2H2. KOH, H2O

1. (COCl)22. CH3CHN2

1A: 68%

(±)-hirsuteneJACS 1980, 102, 6351

JACS 1981, 103, 2744

cyclopentadieneEt2NH, MeOHCHO

CO2Me

1. (CCl3CH2O2CN)22. KO2CN=NCO2K, AcOH3. e- (-1.75 V, Ag/AgCl), LiClO44. K3Fe(CN)6

CH3CN, !85%

CO2MeCO2Me

H

H

H

HO

H

H

H(±)-hirsutene

COCl3 steps

O t-BuLi, vinylbromide CuI-P(NMe2)3, BF3 OEt2.70%

O

OSit-BuMe2

1. Et3BzN+Cl-/KF 2H2O2. TosCl3. LiHMDS

H

H

H(±)-hirsutene

H

H

HO

1. NaBH4,MeOH2. CS2, MeI, NaH, THF3. Bu3SnH, AIBN

Organometallics 1982 1243

J. Chem. Soc. Chem. Commun. 1981, 756

+

O

O

PhH, !

OO

OO

h", EtOAc 500 °C

OO

H

OO

H

H

H

1. H2, Pd/C2. t-BuOK, MeI

OO

H

H

H

OOH

H H

31O °C

14 : 49 : 37

1. NaBH42. MOMCl

H

H

H

OH OMOM

Tatsutas intermediate

J. Chem. Soc. Chem. Commun. 1982, 1252

Br

1. Mg2. CuBr Me2S.

CO2Me

O

3.

OMeO2C NSePh

O O

SnCl4

H H

OMeO2CPhSe

H

H H

OHHO

NSePh

O O1. Bu3P2. RaNi3. Ph3P=CH2

H

H

H(±)-hirsutene


6 steps 5 steps

OOH

H H

H H

OMeO2CPhSe

H

+

2 steps

Bolton 1984Intramolecular nitrone-olefin cycloaddition

Weedon 1985[2+2] cycloaddition followed by ring enlargement


JOC 1984, 49, 5021

O+

TMSTiCl471% (2 : 1)

O

H H

MeNHOH HCl.NaOEt

H

MeN

H

O

1. MeI2. H2, Pd

HH

Me2NOH

2. PCC3. H2, Pd

HH

HO

Nozoe intermediate

(±)-hirsuteneJACS 1985, 107, 1448

1. TMSCCLi2. CsF

IBu3Sn, AIBN

H

H H

Nozoe intermediateJ. Chem. Soc. Chem. Commun. 1985, 1282

O

OH

+

OH

O

OHO

O

O OH

H H

O

H

O

NaBH4, CeCl3

OH1. Ac2O2. LDA, TBDMSCl

OTBDMS

O PhSeCl

OPhSe

O3 stepsCO2H

THPO1. H3O+

2. DIBALH3. Tf2O, py4. nBu4NI

II

Curran 1985Tandem radical cyclization

Wender 1982Arene-olefin cycloaddition

Br+ CHO

1. Mg2. Ac2O, py

AcO 1. h!2. LiAlH4

HO

H

22%

CSA

HH

1. PhSH2. H2, Ir cat.

HH

SPhH1. NaIO4

2. 170 °C, (MeO)3P

HH

H

(±)-hirsuteneTet. Lett. 1982, 23, 3983

71%

mCPBA

HH

OH

80%

H

H

4 steps

Cossy 1987Photoreductive cyclization

AcO

TMS

+

O H

H

O H

H

O

H

H

O

Cl

H

H

OH

H

OH

+

H H

HHO

Tet. Lett. 1987, 28, 4547

1. Pd(OAc)2, P(OiPr)3, 60%2. CH2N2, Pd(OAc)2, 99% H2, PtO2

82%

1. KH2. alkyliodide71%

3 steps

exo/endo 2.9 : 1

h!, Et3N

MeMgBr NiCl2(PPh3)2

H

H H(±)-hirsutene

Paquette 1989Thermal [4+2] and photochemical [2+2] cycloaddition

Nozoe intermediateSynlett 1990, 263

SO2Ph

1. OTMSmesitylene, "

2. Jones

O

H

PhO2S

h!, CH2CH2

O

H

PhO2S

H

H

1. NaHMDS, TBDMSCl2. mCPBA3. Al(Hg)24. Ph3P=CH2

H H

OTBDMS

I2

HO

H

H H

h!

H

Sternbach 1990Intramolecualr Diels-Alder


JOC 1990, 55, 2725

CHOCH(OEt)2

4 steps LiAlH41. 160 °C H CO2H

O3, DMS

OHC

OH OH

OH

O

OH

Cohen 1992[2+1+2] cyclopentannulation

JOC 1992, 57, 1968

HC(SPh)3

1. BuLi2. O

3. sec-BuLi

OLi

CLi(SPh)2

O OLi OLi

PhS SPh

FeCl3

O O

PhS SPh

H

HH

Oppolzer 1994Allylpalladium-alkyne cyclization / carbonylation cascade

O OH

6 steps

CO2Me O

H

CO2Me CO2Me

2. Jones

7 steps

HCHO

HO

AldolH

H H

OH

H H

1. H2, PtO22. Ph3P=CH2

(±)-hirsutene

List 2008Asymmetric transannular aldolization

CO2HHO2C

1. BH32. Swern3. Ph3P=CHCO2Et 70%

EtO2C CO2Et

CO2Me

MeO2C

HH

ON2

O

N2

Mg, MeOH, 80%cis/trans: 1.1 : 1

3 stepsH

O

O

N

F

O H O

O

HH

H

H

H

OH

O

7 stepsH

H H(±)-hirsutene

1. Pd(dba)2, PPh3 CO, AcOH2. CH2N261%

1, H2, Pd2. POCl3

3 steps

H

SePh

MeO2C

Bu3SnH, AIBN

HH

HCO2Me

HH

H4 steps

(±)-hirsuteneTetrahedron 1994, 50, 415

92%

..... for more syntheses

Slothers: J. Chem. Soc. Chem. Commun. 1983, 204Little: JOC 1983, 48, 3139Hua: JACS 1985, 107, 4088Iyoda: J. Chem. Soc. Chem. Commun. 1986, 1049Lacroix: Tet. Lett. 1989, 30, 3529Greene: JACS 1990, 112, 9388Sarkar: Tet. Lett. 1990, 31, 3465Fukumoto: Tet. Lett. 1993, 34, 6099Fitjer: Tetrahedron 1998, 10713Leonhard: Tet. Lett. 1999, 40, 3965Banwell: J. Chem. Soc. Perkin. Trans. 1, 2002, 2439Kim: JACS 2003, 125, 10156Krische: Angew. Chem. 2003, 42, 5855H

H

1. CpRuCl(PPh3)2, 52%2. H2, Pd

NH

F

CO2H

1. NaOH2. Li, NH3, MeI3. Ph3P=CH24. 115 °C

H

H H

(+)-hirsuteneJACS 2008, 130, 6737


Paquette 1979[3+2] Helquist annulation

OO

JOC 1979, 44, 4014

4 stepsMgBr

O

O1. CuBr Me2S

2. MeLi3. SO2Cl, py R

HOAc, H2O (1:1)

OH

+

CHO

1. Jones2. LDA, PhSeCl

O

1. Me2CuLi2. Wolff-Kishner

(±)-isocomene

.

19% 62%

SnCl4, 98%

3. mCPBA4. !

Dauben 1981Acid catalyzed cyclization

O

O

CO2Me

O

CO2MeMeO2C

MeO2C CH2O2Me

CO2Me

CO2Me

O

OO

S

SO

+O

MeO2C

MeO2C

MeOH80%

3 steps

O

CO2Me

O

1. Ketalization2. Partial Hydrolysis3. Wolff-Kishner2. H+

pTsOH88%

1. Nat-amylate, MeI, 84%2. HS(CH2)2SH3. Ph3P=CH2

1. TsOH2. MeI

Paquette IntermediateJOC 1981, 46, 1103

O

Wender 1981Photochemical arene-alkene meta cycloaddition - [3+2] cycloaddition

(±)-isocomene

Br

2 steps+

H235-240 °C14 h, tolene

h"

230 °C, 14 h, toluene

H2, Pd h"

Wenkert 1983#-Oxycyclo-propycarbinol cyclobutanone rearrangement

O

OMe

OOMe

+O

MeO

MeO

H

Me3SiOMeO

JACS 1983, 105, 2030

1. KOEt2. LiAlH4

1.CH2I2, Et2Zn2. Jones

1. LDA, TMSI2. CH2I2, Et2Zn

2 steps

O

H+

3 steps O

LiI

O

(±)-isocomene3 steps 3 steps

Hudlicky 1984[4+1] cyclopentene annulation

O

CO2Et Zn(Cu)BrCH2CH=CHCO2Et

O

N2

CO2Et

CuSO4, Cu(acac)2PhH, Me2S, !

O

CO2EtEtO2C

O

EtO2C

O

CO2EtH

O

Base

CO2Et

CO2H 1. (COCl)22. CH3CH2N2

580 °CPbCO3

Tobe 1985Chelation controlled ring enlargement by epoxide-carbonyl rearrangement

O

1. allene, h", 77%2. LiEt3BH, 87% mCPBA

70%OH

H

OH

H

OLiBr, HMPA81%

O

OHH

1. TBDMSCl, 84%2. LDA, PhSeCl, 82%3. H2O2, 82%

O

ORH

1. LIMe2Cu, 76%2. Wolff-Kishner, 68%3. Jones, 86%4. Ph3P=CH2, 98%5. TsOH, 99%

(±)-isocomeneJ. Chem. Soc. Chem. Commun. 1985, 898

1. H2, PtO22. Ph3P=CH2

NaOEt, EtOH95%

EtO2C(±)-isocomene

76%

Tetrahedron 1981, 37, 4445

OMeHO

OMeLi

MeOHO

1. LiAlH42. TsCl, py3. LiAlH44. TsOH Tet. Lett. 1984, 25, 2447

Dreidring 1986!-Alkynone cyclisation

Snider 1988Intramolecular ketene cycloaddition and Caroll rearrangement

H

O

H

O

+

H

O

H

OAc

Fitjer 1988Thermal controlled rearrangement

1. Cl2C=C=O2. Zn/CH3COOH56%

OPPh3

80%

1. mCPBA2. BF3 OEt2

45%

O

OH

LDAMeI90%

TsOH, 70 °C22h, 27%

Tet. Lett. 1988, 29, 5525

O1. NaBH4, 91%2. diketene, 83% O

OO

LDA, "then CCl4

O

Lee 1991Intramolecular Michael Addition

Bull Korean Chem. Soc. 1991, 12, 392

Helv. Chim. Acta 1986, 69, 659

CO2H2 steps

O

600 °C90%

O

4 steps

3 : 1O

OAc

O

540°C77%

2 steps

OPaquette intermediate

(±)-isocomene

O

O

3 steps

O

O

OO

O

OOKOH, EtOH83%

BrMgCuBr Me2S.

92%

O

OO

R

O

O

3% HCl

O

O

OH

73%

2 stepsO

OO

1. NH3, Li, CH3I2. LDA, CH3I3. LiAlH4

OH

OO

1. POCl3, py2. H+

OPaquetteIntermediate


72%

1. TMSSiCH(CH3)CO2Et LDA2. NaOH, EtOH3. (COCl)2

4 steps

Rawal 1994Photocycloaddition-reductive fragmentation

#

CO2Me

2 steps

h$, PhH89%

O

1. n-BuLi2. Comins reagent

O

O

O

OOH

O1. cyclopentadiene TiCl4, 96%2. LiOH H2O, 94%3. CH2N2, 94%

. OMOM

OMOM

1. i-Pr2NMgI2. Swern

RO

LDBB

RLiOR

LiO

R

O

63%

1. LDA, MeI2. LiBF43. Ph3P, imid. I244%

I

68%

TfO

Me2CuLi84%

(-)-isocomeneJ. Chem. Soc, Chem. Commun. 1994, 1797Pure Appl. Chem. 1996, 68, 675

JOC 1988, 53, 4509

O O OWenkert intermediate

"

31%

HI50%

O Cl

Smith 1981Acid catalyzed rearrangement of !,"-unsaturated ketones (Cargill rearrangement)

O1. h#, ClHCCHCl, 67%2. H+, HO

OH

3. Na, NH3, 78%4. 2% H2SO2, 91%

O OH

Oppolzer 1981Thermal intramolecular ene reaction

O O O

WenderArene-olefin meta cycloaddition

TsOH, PhH, $

OH

OH

1. MeLi2. Jones

1. LiMe2Cu BF3 Et2O, 70%.2. H2C=PPh33. TsOH

(±)-modhephene

88%

7 stepsH

toluene, 250°C

O

H73% single dias.

O

1. H2, Pd/C2. LDA, PhSeBr3. H2O2, 43%

1. MeMgBr, CuS DMS2. PhSeBr, HMPA

.O

Smith intermediate

vinyl acetateh#

AcO AcO

AcO

1. KOH2. BaMnO2

OO KOtBu, MeI+ O

1. Me2CuLi Cl2P(O)NMe2 HNMe2

O(Me2N)2HP

O

1,5-addition

O(Me2N)2HP

O

1,7-addition

(±)-modhephene

2 : 193%


JACS 1981, 103, 194JOC 1982, 47, 1845

Paquette 1981Thermal intramolecular ene reaction

1. dimethylacryloyl chloride, AlCl32. Et3N

O1. SnCl4, $2. RhCl3

O

O

1. 4-chloro-1-TMS-1-butyne CuI, BF3 OEt22. TBAF

.

decalin, 360°C56%

O1. mCPBA2. PPh3=CH2

O1. BF3 OEt22. I2, $

.

3. K2CO3, H2NNH2

(±)-modhephene

O

O

JACS 1981, 103, 722Tetrahedron 1981, 37, 1981

Helv. Chim. Acta 1981, 64, 1575

3. H2O2

JACS 1982, 104, 5805 68% 17%

2. Li, Et3N3. H2, PtO2

Me

Me

Cook 1983Weiss reaction + stereospecific introduction of the methyl function

O

MeO2C

MeO2C

+O

O

Weiss reaction O O

N2

OO

MeO2C

75%CuSO4toluene76%

1. MeLi2. t-BuLi, CO2, HCl, CH2N2

1. MeLi, 85%2. LiI, 95%

JOC 1983, 48, 139

O 2 steps

3. Reduction4. Dehydration

(±)-modhephene

Tobe 1984Chelation controlled regioselective epoxide-carbonyl rearrangement

O

+

OO

O

OO

OBrLiO

OO

OO

O

allene, h#94%

O O

4.5 : 1

1. TMSO(CH2)2OTMS2. mCPBA61%

LiBrHMPA86%

1. MeMgI2. SOCl278%

1. mCPBA2. BF3 OEt2.

2. Wolff-Kishner3. H2SO4

Smith IntermediateJ. Chem. Soc Chem. Comm. 1984, 1259

CurranThe 2nd generation

ClO

1. Pd(PPh3)42. KF3. TMSI, iPr2NEt, 72%

OI

Bu3SnH, AIBN88%

O

1. MeLi2. Jones

O1. Me2CuCNli2. PPh3P=Ch23. TsOH

Mundy 1984Dianion-mediated cyclopentannulation

CO2Me

CO2Me

MeMeLi Me OMeO

O

O

OMeSO3HP2O5

O

MeO2C

MeO2C

+

Br

Br

LDA51%

CO2Me

CO2Me

4 steps80%

Smith Intermediate

30%

JOC 1985, 50, 5727Tet Lett 1984, 25, 4619


Mash 1988First enantioselective synthesis: Diastereoselective cyclopropanation

O

2steps

OO

RR

+

O H

Tet. Lett. 1988, 29, 2147

8 : 1

1. aq. HCl2. TMSI

O H

I

1. Ketalization2. LiCH2CCTMS3. H3O+

4. TBAF

Paquette Intermediate

OO

RR

(+)-modhephene

ZnClTMS

(±)-modhephene

CurranThe 3rd generation

O

OBn

8 steps

CO2H

JACS 1990, 112, 5601

Tetrahedron 1993, 49, 755

Curran 1990Radical addition - fragmentation

SnMe3

CO2Me

LDA,89% (1 : 1)

SnMe3

Br BrBr

CO2Me

Bu3SnH, AIBN

90%CO2Me

1. NaOH, (COCl)22. TiCl4

O

BrBu3SnH, AIBN

85%O

Me2Zn, TiCl4

Mundys Intermediate

BrTMS

(±)-modhephene

Fitjer 1988Kinetic controlled rearrangement

OHTsOH, 10 min62%

Tet. Lett. 1988, 29, 5525(±)-modhephene

ClCOCOCl

NO

S COTh

!

CH2SPy

1. NaIO42. RuCl3 NaIO4O

(±)-modhephene

4 steps

Kraus 1991Rearrangement of bridgehead bromides

O

Br

CO2Me

Br

CO2Me

O

CO2Me

OR


H2SO4, MVK77%

RLi70%

R = (MeO)2POCH2

Ir, H2

CO2Me

OR

O

O

MeO

KH

1. MeLi2. H+

Curran intermediateJOC 1991, 56, 4147

modhehene /epi-modhephene4:1

Sha 1991Intramolecular radical cyclization

Bu3SnH, AIBN

O1. Ph3P=CH2, 72%2. I2, PhH, 81%

85%

+

Tet. Lett. 1990, 31, 3745

MgBrCuI, TMSCl80%

NaI, mCPBA67%

Suri 1993Intramolecular alkylation

O

CO2CH3

5 steps

CHO

OO

OO

OO

O

CH2Br

9 steps LDA-HMPA-THF79%

Kim 1996Tandem Radical cyclization reaction of N-ariridinyl iminesThe 1st generation

O

CO2Et 4 stepsBu3SnH, AIBNPhH, SiO2, 85%

NN

Ph

Br

NN

Ph

NN

Ph

NN

Ph

Oppolzer intermediate

OO

O O

OHCOHC

1. DOWEX, 95%2. KIO4-Et2O, 80%

O

(Ph3P)3RhCl60%

Tet Lett 1993, 34, 8321Curran intermediate

1. mCPBA2. Et2NLi, MnO2

O O

3.5 : 1

2nd generation

NN

Ph

+

Kim 3rd generation

NN

Ph

HO

9 : 1

HO

1. Swern

Bu3SnH, AIBN 4 stepsO

Curran intermediateChem. Commun. 1996, 1539

(±)-modhephene

Bu3SnH, AIBN2. MeMgBr

Bull. Korean Chem. Soc. 1999, 20, 269

O TMSO IO

Rawal 1997Photocycloaddition-reductive fragmentation

CO2Me

2 stepsh!, PhHcorex filters89%

O

LDA, PhSeCl

(±)-modhephene

O

LDBB, Et3Al, 86%

HO

61%

SePhO

Et3B, air61%

O

OEt3Al

RO

Et3AlO

Et3AlRO

Et3AlR R


Chem. Commun. 1997, 2381

SnBu3

OH

SnBu3

OH

SnBu3

OH OH

1. OsO42. NaIO4, 78% over 2 steps3. MsCl, Et3N, 87%

O6 steps

O1. TMSOTf, Et3N2. O3, PPh3, HIO4

3. TMSCHN24. LiAlH4

OH

OH+

OHOH

CHO

(±)-modhephene

1. Swern 2. AcOH-piperidine80% over 2 steps

Pattenden 1998Tandem transannulation - cyclization

1. Me2CuLiCN2. Ph3P=CH23. TsOH

OH

O

5 steps

O

SI

Bu3SnH, AIBNO

OOOO

56%

2 steps

O

N2

CuSO4 O

Cook intermediateTet. Lett, 1998, 39, 6975

Bahn 2005Tandem radical cyclization

O

CO2Me8 steps

Bu3SnH, AIBN, SiO2, 70%

OH OHSnBu3

Tet. Lett. 2005, 46, 14552.5 : 1

4 steps

PDC

baran gm 03/17/12 triquinanes: hirsutene, isocomene ...baran gm 03/17/12 triquinanes: hirsutene,...

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